Among gynecological malignancies occurring in American women, ovarian cancer most frequently causes death. The malignancy remains confined to the peritoneal cavity during practically its entire clinical course. Characteristically the tumor disseminates throughout the peritoneal cavity producing acites and tumor foci on multiple peritoneal surfaces. The disease cannot be effectively cured surgically and chemotherapy is increasingly the primary treatment. Because ovarian tumors generally remain in the peritoneal cavity, chemotherapeutic agents may be administered systemically by intravenous injection or by direct infusion into the peritoneal cavity thus by-passing the circulatory system as the route for initially exposing the tumor to the chemotherapeutic agent.
The use of monoclonal antibodies against antigens associated with cancerqus ovarian tissues has been reported to only a limited extent. An antibody to human transferrin receptor linked to Pseudomonas exotoxin has been reported to have cytotoxic activity in certain human ovarian cell lines. Pirker et al., "Anti-transferrin
receptor antibody linked to Pseudomonas exotoxin; a model imrunotoxin in human ovarian carcinoma cell lines", Cancer Res. 45:751-757 (1985). Anti-transferrin monoclonal antibodies that inhibit the binding of transferrin to the transferrin receptor are the subject of U.S. Pat. No. 4,434,156. The anti-transferrin monoclonal antibodies of the present invention are different from those disclosed in U.S. Pat. No. 4,434,156. Although the anti-transferrin antibody of the present invention binds the transferrin receptor, it does not inhibit the binding of transferrin to the transferrin receptor. Schlom et al., U.S. Pat. No. 4,522,918 discloses a method of producing monoclonal antibodies against certain human breast cancer tumors using soluble extracts of human breast cancer.
A principal aspect of the invention concerns murine monoclonal antibodies that:
(a) bind human ovarian cancer tissue frozen sections; PA1 (b) are IgGs or IgMs; PA1 (c) when bound to a cytotoxic moiety, have an ID.sub.50 of 10 nM or less against at least one ovarian cancer cell line selected from the group consisting of OVCAR-2, OVCAR-3, OVCAR-4, OVCAR-5 or A1847; or PA1 when bound to a cytotoxic moiety extend the survival time of mammals carrying human ovarian tumors; or when bound to a cytotoxic protein retard the rate of growth of human ovarian tumors carried by such mammals. PA1 (a) the above described monoclonal antibodies, and PA1 (b) a cytotoxic moiety.
Preferred embodiments of these antibodies are those designated 2G3, 9C6, 33F8, 44B2, 44F4, 120H7, 200F9, 204F4, 219F3, 245E7, 260F9, 266B2, 280D11, 317G5, 369F10, 388D4, 421E8, 451C3, 454A12, 454C11, 650E2, 788G6, 871E3, and functional equivalents thereof.
The rurine x murine hybridomas i.e., hybridomas prepared from spleenocytes of immunized mice and a murine tumor partner such as a murine myeloma that produce the above described antibodies and progeny of those hybridomas are other aspects of the invention.
Another aspect of the invention relates to immunotoxins that are conjugates of
Another aspect of the invention concerns methods of extending the survival time of mammals bearing human ovarian tumor cells by administering to such mammal an amount of an immunotoxin described above effective to extend the life of such mammal.
Yet another aspect of the invention concerns methods of killing human ovarian tumor cells by contacting such cells with a cytocidally effective amount of the immunotoxin described above.
A further aspect of the invention concerns methods of retarding the rate of growth of human ovarian tumor cells carried by a mammal by administering to such mammal a tumor cell growth-retarding amount of the imaunotoxin described above.
The invention also relates to conjugates comprising recombinant ricin toxin A chain and a target cell binding moiety or "surogate B moiety".